Methamphetamine (mAMPH) is a highly addictive psychostimulant. In many regions of the United States, it is second only to alcohol and marijuana as the most frequently used drug, often outpacing both heroin and cocaine abuse. Despite an increased number of studies recently devoting attention to measuring mAMPH effects on learning and memory, no systematic investigation has been conducted on mAMPH's impact on cognitive flexibility in either an animal model or in humans. Cognitive flexibility is of vital importance to the success of an organism and refers to the ability to shift strategy given a new set of circumstances. If mAMPH impacts functioning of the orbitofrontal cortex (OFC), as is currently posited, then mAMPH likely has an impact on flexible cognition. In addition, there is now evidence for serotonergic modulation of this flexible cognition and given that neuronal serotonin integrity is compromised in mAMPH abusers (and mAMPH-treated animals), this is a timely issue. We propose to study the effects of mAMPH on flexible cognition using a touch screen-based operant procedure sensitive to pharmacological manipulation in rodents. Our measures of flexible cognition are reversal learning and extinction, two separate tasks sensitive to both OFC recruitment and serotonergic modulation and that are well-equipped with a host of auxiliary measures of motivation, attention, and inhibitory control. Our long-term goal is to reconcile our understanding of the neural circuitry that subserves flexible cognition with the pathological effects of drugs of abuse. To begin to accomplish our long-term goal, two specific aims are proposed: 1) to establish baseline cognitive flexibility performance in untreated rats and 2) to compare the effects of a binge regimen and an escalating, neuroprotective dose regimen of mAMPH on cognitive flexibility and the OFC. Results arising from this project will enhance our understanding of the impact of mAMPH on flexible cognitive processes and increase our ability to identify therapeutic targets to ameliorate the poor decision making arising from mAMPH abuse. At best, a rescued cognitive flexibility could aid mAMPH addicts in remaining abstinent. Public Health Relevance: Methamphetamine is a highly addictive psychostimulant and a growing public health concern, with a record of nearly 1.4 million people over the age of 12 using methamphetamine in the United States in 2005. Those addicted to this substance make poor, disadvantageous choices and relapse often. The long-term goal of this project is to provide knowledge about the effects of methamphetamine on decision making and the brain.